Alendronate (Alendronate Sodium) - Description and Clinical Pharmacology

DESCRIPTION

Alendronate Sodium is bisphosphonate that acts as a specific inhibitor of osteoclastmediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.

Alendronate Sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.

The empirical formula of Alendronate Sodium is C₄H₁₂NNaO₇P₂•3H₂O and its formula weight is 325.12. The structural formula is:

Alendronate Sodium, USP is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.

Alendronate Sodium Tablet for oral administration contain 6.53, 13.05, 45.68, or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5, 10, 35, and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, and magnesium stearate.

CLINICAL PHARMACOLOGY

Mechanism of Action

Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [³H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [³H] alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

Pharmacodynamics

Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.

Osteoporosis in Postmenopausal Women

Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.

Daily oral doses of Alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.

Long-term treatment of osteoporosis with Alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type I collagen, by approximately 50% and 70% respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received Alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with Alendronate. In osteoporosis treatment studies Alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25% to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies Alendronate 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15% respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly Alendronate 70 mg for the treatment of osteoporosis and once weekly Alendronate 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steadystate, despite the progressive increase in the total amount of alendronate deposited within bone.

As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with Alendronate. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of Alendronate 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward pre-study levels during years three through five. Similar reductions were observed with Alendronate 5 mg/day. In one-year studies with once weekly Alendronate 35 mg and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to Alendronate but also a decrease in renal phosphate reabsorption.

Osteoporosis in men

Treatment of men with osteoporosis with Alendronate 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly Alendronate 70 mg.

Glucocorticoid-induced Osteoporosis

Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation.

In clinical studies of up to two years’ duration, Alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type I collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition of bone resorption, Alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).

Paget's disease of bone

Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

Alendronate decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, Alendronate 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, Alendronate induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.

Pharmacokinetics

Absorption

Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.

Alendronate Sodium 70 mg oral solution and Alendronate Sodium Tablet 70 mg are equally bioavailable.

A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.

Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Distribution

Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.

Metabolism

There is no evidence that alendronate is metabolized in animals or humans.

Excretion

Following a single intravenous dose of [¹⁴C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with Alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.

Specific Populations

Gender: Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women.

Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.

No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. Alendronate is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.

Hepatic Impairment: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.

Drug Interactions

Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H₂-antagonists is unknown.

In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).

Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1,3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to approximately 0.1 to 1 times a maximum recommended daily dose of 40 mg (Paget’s disease) based on surface area, mg/m². The relevance of this finding to humans is unknown.

Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to approximately 0.3 and 1 times a 40 mg human daily dose based on surface area, mg/m². The relevance of this finding to humans is unknown.

Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.

Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (approximately 1 times a 40 mg human daily dose based on surface area, mg/m²).

Animal Toxicology and/or Pharmacology

The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

CLINICAL STUDIES

Treatment of Osteoporosis in Postmenopausal Women

Daily Dosing

The efficacy of Alendronate 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture.

Effect on Fracture Incidence

To assess the effects of Alendronate on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of Alendronate (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with Alendronate experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received Alendronate had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).

The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion.

Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture)

This randomized, double-blind, placebo-controlled, 2027-patient study (Alendronate, n=1022; placebo, n=1005) demonstrated that treatment with Alendronate resulted in statistically significant reductions in fracture incidence at three years as shown in  Table 6.

Table 6: Effect of Alendronate on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral fracture at baseline)

	Percent of Patients
	Alendronate (n=1022)	Placebo (n=1005)	Absolute Reduction in Fracture Incidence	Relative Reduction in Fracture Risk %
Patients with: Vertebral fractures (diagnosed by X-ray) *
≥ 1 new vertebral fracture	7.9	15.0	7.1	47 †
≥ 2 new vertebral fractures	0.5	4.9	4.4	90 †
Clinical (symptomatic) fractures
Any clinical (symptomatic) fracture	13.8	18.1	4.3	26 ‡
≥ 1 clinical (symptomatic) vertebral fracture	2.3	5.0	2.7	54 §
Hip fracture	1.1	2.2	1.1	51 ¶
Wrist (forearm) fracture	2.2	4.1	1.9	48 ¶

* Number evaluable for vertebral fractures: Alendronate, n=984; placebo, n=966. 

† p<0.001, ‡ p=0.007, § p<0.01, ¶ p<0.05.

Furthermore, in this population of patients with baseline vertebral fracture, treatment with Alendronate significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%).

In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on Alendronate, p=0.047.  Figure 1 displays the cumulative incidence of hip fractures in this study.

Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture)

This randomized, double-blind, placebo-controlled, 4432-patient study (Alendronate, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to Alendronate. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in the  table 7 for the patients with osteoporosis.

Table 7: Effect of Alendronate on Fracture Incidence in Osteoporotic* Patients in the Four-Year Study of FIT (patients without vertebral fracture at baseline)

	Percent of Patients
	Alendronate (n=1545)	Placebo (n=1521)	Absolute Reduction in Fracture Incidence	Relative Reduction in Fracture Risk (%)
Patients with: Vertebral fractures (diagnosed by X-ray)†
≥ 1 new vertebral fracture	2.5	4.8	2.3	48‡
≥ 2 new vertebral fractures	0.1	0.6	0.5	78§
Clinical (symptomatic) fractures
Any clinical (symptomatic) fracture	12.9	16.2	3.3	22¶
≥ 1 clinical (symptomatic) vertebral fracture	1.0	1.6	0.6	41(NS)#
Hip fracture	1.0	1.4	0.4	29 (NS)#
Wrist (forearm) fracture	3.9	3.8	-0.1	NS#

* Baseline femoral neck BMD at least 2 SD below the mean for young adult women.

† Number evaluable for vertebral fractures: Alendronate, n=1426; placebo, n=1428.

‡ p<0.001. § p=0.035. ¶ p=0.01. # Not significant. This study was not powered to detect differences at these sites.

Fracture results across studies

In the Three-Year Study of FIT, Alendronate reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034).

Alendronate reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, Alendronate reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).

Thus, Alendronate reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.

Effect on Bone Mineral Density

The bone mineral density efficacy of Alendronate 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration.

Figure 2  shows the mean increases in BMD of the lumbar spine femoral neck, and trochanter in patients receiving Alendronate 10 mg/day relative to placebo-treated patients at three years for each of these studies.

At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received Alendronate 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results). In the two-year extension of these studies, treatment of 147 patients with Alendronate 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Alendronate was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).

In patients with postmenopausal osteoporosis treated with Alendronate 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups.

Bone Histology

Bone histology in 270 postmenopausal patients with osteoporosis treated with Alendronate at doses ranging from 1 to 20 mg alendronate/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with Alendronate is of normal quality.

Effect on Height

Alendronate, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.

Weekly Dosing

The therapeutic equivalence of once weekly Alendronate 70 mg (n=519) and Alendronate 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10 mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to treat analysis were consistent with the primary analysis of completers.

Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT)

The effects on BMD of treatment with Alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or Alendronate alone (both 6.0%).

The effects on BMD when Alendronate was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of Alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).

In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.

Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with Alendronate and HRT, 94% on Alendronate alone, and 78% on HRT alone. The long-term effects of combined Alendronate and HRT on fracture occurrence and fracture healing have not been studied.

Prevention of Osteoporosis in Postmenopausal Women

Daily Dosing

Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40-60 years of age. One thousand six hundred nine patients (Alendronate 5 mg/day; n=498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (Alendronate 5 mg/day; n=88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, Alendronate 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see Figure 4). In addition, Alendronate 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Alendronate 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.

Bone Histology

Bone histology was normal in the 28 patients biopsied at the end of three years who received Alendronate at doses of up to 10 mg/day.

Weekly Dosing

The therapeutic equivalence of once weekly Alendronate 35 mg (n=362) and Alendronate 5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35 mg once-weekly group (n=307) and 3.2% (2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.

Treatment to Increase Bone Mass in Men with Osteoporosis

The efficacy of Alendronate in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.

Daily Dosing

A two-year, double-blind, placebo-controlled, multicenter study of Alendronate 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving Alendronate 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with Alendronate also reduced height loss (Alendronate, -0.6 mm vs. placebo, -2.4 mm).

Weekly Dosing

A one-year, double-blind, placebo-controlled, multicenter study of once weekly Alendronate 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a BMD T-score less than or equal to -2 at the lumbar spine and less than or equal to -1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving Alendronate 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study.

In both studies, BMD responses were similar regardless of age (greater than or equal to 65 years vs. less than 65 years), gonadal function (baseline testosterone less than 9 ng/dL vs. greater than or equal to 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or equal to -2.5 vs. greater than -2.5).

Treatment of Glucocorticoid-Induced Osteoporosis

The efficacy of Alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational [which also included Alendronate 2.5 mg/day]). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D.  Figure 5  shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving Alendronate 5 mg/day for each study.

After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received Alendronate 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%),  and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with Alendronate 5 mg/day. The increases in BMD with Alendronate 10 mg/day were similar to those with Alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with Alendronate 10 mg/day were greater than those with Alendronate 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate was effective regardless of dose or duration of glucocorticoid use. In addition, Alendronate was similarly effective regardless of age (less than 65 vs. greater than or equal to 65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications.

Bone histology was normal in the 49 patients biopsied at the end of one year who received Alendronate at doses of up to 10 mg/day.

Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with Alendronate 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body.

After one year, 2.3% of patients treated with Alendronate 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with Alendronate (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (Alendronate 0.7% vs. placebo 6.8%).

Treatment of Paget's Disease of Bone

The efficacy of Alendronate 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget’s disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day.  Figure 6  shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.

At six months the suppression in alkaline phosphatase in patients treated with Alendronate was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline greater than or equal to 60%) occurred in approximately 85% of patients treated with Alendronate in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Alendronate was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).

Bone histology was evaluated in 33 patients with Paget’s disease treated with Alendronate 40 mg/day for 6 months. As in patients treated for osteoporosis [see Clinical Studies], Alendronate did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with Alendronate, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with Alendronate is of normal quality.